The present invention is concerned with certain diamidines and a bis-imidazoline having antiprotozoal activity, and their use in the control of trypanosomiasis and/or babesiosis in mammals, particularly in cattle.
Trypanosomiasis is a disease of man and animals caused by flagellate blood borne protozoan parasites. The disease is encountered mainly in Africa, where it is transmitted by the Tse Tse fly. Animal typanosomiasis caused by Trypanosoma congolense and T. vivax, is considered to be the limiting factor for livestock production in most of the African Continent. Although trypanosomiasis can be fatal to man, its devastating effect on meat producing animals has indirectly caused much more human suffering due to protein starvation. Babesiosis is another hemo-protozoan disease of livestock and is economically important in the tropical and subtropical regions of the world.
Previously reported diamidines having antiprotozoal activity include ##STR2## wherein Z is:
--NH--N.dbd.N-- (diminazene, see The Merck Index, 9th Ed., monograph No. 3258); PA1 --CH.dbd.CH-- (stilbamidine, loc. cit., monograph No. 8597; Ashley et al. [A], J. Chem. Soc., pp. 103-116, 1942); PA1 --CH.dbd.CH--CH.dbd.CH-- (Ashley et al. [A]). PA1 --O(CH.sub.2).sub.p O--, where p=1 to 10 (Ashley et al. [A]; when p=5, pentamidine, loc. cit., monograph No. 6912); or PA1 --O-- (phenamidine, loc. cit., monograph No. 6994); and ##STR3## wherein Y is O, S, NH, NCH.sub.3 or CH.sub.2 (Dann et al. [A], Ann. vol. 749, pp. 68-89, 1971; Dann, U.S. Pat. Nos. 3,652,591 and 3,689,506). PA1 R is (C.sub.1 -C.sub.3)alkyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, benzyl or 2-, 3- or 4-picolyl; with the provisos that when R is 4-picolyl, m is 1; and when R is methyl and m is 1, n is other than O; PA1 and the pharmaceutically-acceptable acid addition salts thereof. Such salts include, but are not limited to, those formed with HCl, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, propionic acid, succinic acid, maleic acid, citric acid, methanesulfonic acid, isethionic acid, p-toluenesulfonic acid and aceturic acid. The preferred salts, because of their more consistent biological activity, are those with HCl.
On the other hand, compounds failing to protect (cure) mice against a protozoal infection include those compounds of the formula (I) wherein Z is --CO--, --CHOH--, --CH.sub.2 CO--, --CH.dbd.CHCO--, --NHCO--, --SO.sub.2 --, --NHSO.sub.2 --, --S--S--, --N.dbd.N--, --NHNH--, --N.dbd.N(O)--, --CH.sub.2 --, --S--, --CH.sub.2 NH--, --NHCONH--, --OCH.sub.2 OCH.sub.2 O--, --CH.sub.2 SCH.sub.2 --, --CH.sub.2 NHCH.sub.2 --, --OCH.sub.2 (p--C.sub.6 H.sub.4)CH.sub.2 O-- or --CH.sub.2 O(p--C.sub.6 H.sub.4)OCH.sub.2 --; in spite of the fact that the compounds having the last seven values of Z did show an early and favorable effect on the level of trypanosomes in the peripheral blood stream (Ashley et al. [A]; Ashley et al. [B], J. Chem. Soc., pp. 3089-3093, 1957). Furthermore, replacement of --O(CH.sub.2).sub.4 O-- in (I) with an olefinic variant, -- OCH.sub.2 CH.dbd.CHCH.sub.2 O--, leads to considerable less activity against T. rhodesiense and inactivity against T. congolense (Ashley et al. [C], J. Chem. Soc., pp. 1668-1671, 1957); substitution of the bridging group in diminazene with a methyl group, i.e., Z+--N(CH.sub.3)N.dbd.N--, reduces activity by about 75% (Ashley et al. [B]); and the m, m'-isomers of the compounds (I) wherein Z is --O(CH.sub.2).sub.3 O-- or --O(CH.sub.2).sub.5 O-- are about half as active as the p, p'-isomers.
Among the diamidines reported to haVe antiprotozoal activity are a number of compounds having the formula (I) wherein Z is represented by one of the following 5-membered heterocyclic groups: ##STR4## where Q is O, S, NH or N(CH.sub.3); ##STR5## where Q' is S, NH or CH.sub.2 ; ##STR6## (Das et al. [A], J. Med. Chem. Vol. 20, pp. 531-536, 1977; Das et al. [B], ibid., Vol. 20, pp. 1219-1221, 1977; Das et al. [C], ibid., Vol. 23, pp. 578-581, 1980; Dann et al. [B], Ann. pp. 160-194, 1975). For a similar compound (I), wherein Z is ##STR7## reports concerning activity are conflicting. Thus, against T. rhodesiense infections in mice, Das et al. [C] reports no more than a minor increase in mean survival time, at a dose of 40 mg/kg; while earlier Dann et al. [B]reported minimum curative dose of 1-10 mg/kg for the same compound against the same microorganism.
It has also been previously noted by Berg (J. Chem. Soc., pp. 5097-5101, 1961) that the compound of the formula (I) wherein Z is --NHCONH-- is lacking in activity, although the corresponding meta isomer: ##STR8## showed considerable activity. Berg further noted that replacement of the --NHCONH-- group in (III) with --NHC(.dbd.NH)NH--, --NHC(.dbd.NCH.sub.3)NH-- or --NHCSNH-- led to lowered activity.
The bis-imidazoline compound of the formula ##STR9## presently discovered to have antiprotozoal activity, has been previously reported to have antifungal activity (Anne et al., Antimicrobial Agents and Chemotherapy, vol. 18, pp. 231-239, 1980), and to inhibit oncornaviral DNA polymerase (De Clercq et al., J. Med. Chem., Vol. 23, pp. 787-795, 1980). Neither Anne et al. nor DeClercq et al. describe compound (IV) per se, nor do they provide a method of preparation therefor. For this reason, a detailed preparation method for this compound is included below.